One of the most common causes of medically refractory pediatric epilepsy is focal dysplasia of the cerebral cortex. Until recently, the basis of this disorder remained a medical mystery. Genetic studies of the most severe form of focal dysplasia, hemimegalencephaly, in which one entire cerebral hemisphere is enlarged in size, led to the identification of gain-of-function somatic mutations in the phosphatidylinositol-3-kinase (PI3K)–protein kinase B (Akt) and mammalian target of rapamycin (mTOR) signaling pathways (Table 1, Fig. 2). We now know that mutations in mTOR are the single largest contributor to focal dysplasia in pediatric epilepsy (49–51). Similarly, germline mutations in one allele of the TSC1 or TSC2 gene confer susceptibility to tuberous sclerosis, a disease characterized by facial and skin lesions, seizures, intellectual disability, cardiac and renal tumors, and cortical tubers (52). Because the Tsc1 and Tsc2 proteins are negative regulators of the mTOR-signaling pathway, a second somatically acquired mutation is required for disease onset. Somatic mutations that mildly activate the mTOR-signaling pathway also cause symmetrical overgrowth syndromes such as megalencephaly-capillary malformation syndrome, megalencephaly, and certain forms of polymicrogyria (49–51).
